IN SILICO ANALYSIS OF TECOVIRIMAT A REPURPOSED DRUG AGAINST THE MONKEYPOX VIRUS, ITS OFF-TARGET HUMAN PROTEINS, AND IMPACT ON HUMAN HEALTH

JANVI AGGARWAL; POONAM SHARMA

doi:10.22159/ijap.2023v15i6.49248

Authors

JANVI AGGARWAL Department of Zoology, Gargi College, University of Delhi, India https://orcid.org/0009-0009-1739-8004
POONAM SHARMA Department of Zoology, Gargi College, University of Delhi, India https://orcid.org/0000-0002-7694-3369

DOI:

https://doi.org/10.22159/ijap.2023v15i6.49248

Keywords:

Monkeypox, Tecovirimat, p37 protein, Rheumatoid arthritis, Alzheimer's disease

Abstract

Objective: In this study, in silico analysis of human off-target proteins of tecovirimat, an investigational drug reported to stop monkey pox virus infection by binding to a protein that the virus uses to enter host cells was performed to better understand its off-target long-term and short-term effects on other important biological processes in patients.

Methods: The target and off-target proteins of the drug, as well as their characteristics, protein-protein interactions, and the pathways they are involved in, were thoroughly analyzed using a number of databases, including Drug Bank, the NCBI Gene Database, BLAST, the UCSC Gene Sorter, Gene MANIA, STRING, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database.

Results: The current study showed that although the repurposing drug tecovirimat aids in the treatment of patients with monkeypox by binding to the viral p37 protein, it can also accidentally interfere with vital biological processes by interacting with off-target proteins or by indirectly interfering with the proteins that interact with these target proteins.

Conclusion: The findings highlight the importance of extensively assessing and evaluating all repurposed drugs for their off-target effects before making them available to the general public.

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References

Farahat RA, Abdelaal A, Shah J, Ghozy S, Sah R, Bonilla Aldana DK. Monkeypox outbreaks during COVID-19 pandemic: are we looking at an independent phenomenon or an overlapping pandemic? Ann Clin Microbiol Antimicrob. 2022 Jun 15;21(1):26. doi: 10.1186/s12941-022-00518-2, PMID 35706004.

Patel M, Mazumder R, Kaushik KK, Debnath A, Mishra R, Pal S. A brief description of COVID-19 pulmonary viral infection and repurposing of drugs for its treatment. Int J App Pharm. 2022;14(5):22-31. doi: 10.22159/ijap.2022v14i5.45168.

Rabaan AA, Abas AH, Tallei TE, Al-Zaher MA, Al-Sheef NM, Fatimawali A-NEZ. Monkeypox outbreak 2022: what we know so far and its potential drug targets and management strategies. J Med Virol. 2023 Jan;95(1):e28306. doi: 10.1002/jmv.28306, PMID 36372558.

Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 Jan 1;34:D668-72. doi: 10.1093/nar/gkj067, PMID 16381955.

Kent WJ, Hsu F, Karolchik D, Kuhn RM, Clawson H, Trumbower H. Exploring relationships and mining data with the UCSC gene sorter. Genome Res. 2005 May;15(5):737-41. doi: 10.1101/gr.3694705, PMID 15867434.

Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-61. doi: 10.1093/nar/gkw1092, PMID 27899662.

Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S. The string database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021 Jan 8;49(D1):D605-12. doi: 10.1093/nar/gkaa1074, PMID 33237311.

MSS, Dinesh S, Sharma S. Prediction of high-risk NSSNPS associated with WISP3 gene expression: an in silico study. Int J App Pharm. 2023;15(5):161-70. doi: 10.22159/ijap.2023v15i5.48269.

Gonzalez AC, Schweizer M, Jagdmann S, Bernreuther C, Reinheckel T, Saftig P. Unconventional trafficking of mammalian phospholipase D3 to lysosomes. Cell Rep. 2018 Jan 23;22(4):1040-53. doi: 10.1016/j.celrep.2017.12.100, PMID 29386126.

Cappel C, Gonzalez AC, Damme M. Quantification and characterization of the 5′ exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay. J Biol Chem. 2021 Jan-Jun;296(96):100152. doi: 10.1074/jbc.RA120.015867, PMID 33288674. PMCID PMC7857491.

Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature. 2014 Jan 23;505(7484):550-4. doi: 10.1038/nature12825, PMID 24336208. PMCID PMC4050701.

Tan MS, Wang P, Ma FC, Li JQ, Tan CC, Yu JT. Common variant in PLD3 influencing cerebrospinal fluid total tau levels and hippocampal volumes in mild cognitive impairment patients from the ADNI cohort. J Alzheimers Dis. 2018;65(3):871-6. doi: 10.3233/JAD-180431, PMID 30103332.

Lambert JC, Grenier-Boley B, Bellenguez C, Pasquier F, Campion D, Dartigues JF. PLD3 and sporadic Alzheimer’s disease risk. Nature. 2015 Apr 2;520(7545):E1. doi: 10.1038/nature14036, PMID 25832408.

Engelman CD, Darst BF, Bilgel M, Vasiljevic E, Koscik RL, Jedynak BM. The effect of rare variants in TREM2 and PLD3 on longitudinal cognitive function in the Wisconsin registry for Alzheimer’s prevention. Neurobiol Aging. 2018 Jun;66(177):177.e1-5. doi: 10.1016/j.neurobiolaging.2017.12.025, PMID 29395285, PMCID PMC5924624.

Nygaard HB, Erson Omay EZ, Wu X, Kent BA, Bernales CQ, Evans DM. Whole-exome sequencing of an exceptional longevity cohort. J Gerontol A Biol Sci Med Sci. 2019 Aug 16;74(9):1386-90. doi: 10.1093/gerona/gly098, PMID 29750252. PMCID PMC6696723.

Van Acker ZP, Bretou M, Sannerud R, Damme M, Annaert W. Deficiency of the lysosomal exonuclease PLD3 impacts the degradative route. Alzheimers Dem. 2021 Dec;17(S3) Suppl 3:e050868. doi: 10.1002/alz.050868.

Otani Y, Yamaguchi Y, Sato Y, Furuichi T, Ikenaka K, Kitani H. PLD$ is involved in phagocytosis of microglia: expression and localization changes of PLD4 are correlated with activation state of microglia. PLOS ONE. 2011;6(11):e27544. doi: 10.1371/journal.pone.0027544, PMID 22102906.

Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumor-associated macrophages. Immunology. 2013 Feb;138(2):93-104. doi: 10.1111/imm.12023, PMID 23113570, PMCID PMC3575762.

Gao L, Zhou Y, Zhou SX, Yu XJ, Xu JM, Zuo L. PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells. Oncol Rep. 2017 Jan;37(1):408-16. doi: 10.3892/or.2016.5216, PMID 27840999.

Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K. PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population. Arthritis Rheum. 2013 Feb;65(2):472-80. doi: 10.1002/art.37777, PMID 23124809.

Chen WC, Wang WC, Okada Y, Chang WP, Chou YH, Chang HH. rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis. Oncotarget. 2017 Jul 18;8(38):64180-90. doi: 10.18632/oncotarget.19419, PMID 28969061. PMCID PMC5609993.

Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet. 2012 Mar 25;44(5):511-6. doi: 10.1038/ng.2231, PMID 22446963.

Nelson RK, Ya Ping J, Gadbery J, Abedeen D, Sampson N, Lin RZ. Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway. Sci Rep. 2017 Aug 22;7(1):9112. doi: 10.1038/s41598-017-09852-4, PMID 28831159. PMCID PMC5567230.

Bradshaw RA, Dennis EA. editors. Handbook of cell signaling. Academic press; 2009 Nov 3.

Liu X, Zang C, Wu Y, Meng R, Chen Y, Jiang T. Homeodomain-interacting protein kinase HIPK4 regulates phosphorylation of manchette protein RIMBP3 during spermiogenesis. J Biol Chem. 2022;298(9):102327. doi: 10.1016/j.jbc.2022.102327, PMID 35931115, PMCID PMC9440445.

Stoica C, Ferreira AK, Hannan K, Bakovic M. Bilayer forming phospholipids as targets for cancer therapy. Int J Mol Sci. 2022 May 9;23(9):35563655. doi: 10.3390/ijms23095266, PMID 35563655, PMCID PMC9100777.

Dushianthan A, Cusack R, Grocott MPW, Postle AD. Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome. J Lipid Res. 2018 Jun;59(6):1034-45. doi: 10.1194/jlr.P085050, PMID 29716960. PMCID PMC5983399.

Griffith JR. Williams textbook of endocrinology: P. Reed Larsen, MD, Henry M. Kronenberg, MD, Shlomo Melmed MD, Kenneth S, Polonsky MD, Philadelphia WB. Saunders Company, 2003. J Pediatr Adolesc Gyneco. 2004 Jun 1;17(3):217-8.

Bernard Pierrot I, Gruel N, Stransky N, Vincent Salomon A, Reyal F, Raynal V. Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer. Cancer Res. 2008 Sep 1;68(17):7165-75. doi: 10.1158/0008-5472.CAN-08-1360, PMID 18757432.

Tollefsbol T, editor. Handbook of epigenetics: the new molecular and medical genetics. Academic Press; 2017 Jul 10.

Li J, Xin Y, Li J, Chen H, Li H. Phosphatidylethanolamine N-methyltransferase: from functions to diseases. Aging Dis. 2023;14(3):879-91. doi: 10.14336/AD.2022.1025, PMID 37191416.

Jain S, Zhang X, Khandelwal PJ, Saunders AJ, Cummings BS, Oelkers P. Characterization of human lysophospholipid acyltransferase 3. J Lipid Res. 2009 Aug;50(8):1563-70. doi: 10.1194/jlr.M800398-JLR200, PMID 19351971. PMCID PMC2724057.

Werner ER, Keller MA, Sailer S, Lackner K, Koch J, Hermann M. The TMEM189 gene encodes plasmanylethanolamine desaturase, which introduces the characteristic vinyl ether double bond into plasmalogens. Proc Natl Acad Sci USA. 2020 Apr 7;117(14):7792-8. doi: 10.1073/pnas.1917461117, PMID 32209662. PMCID PMC7149458.